This invention relates to a process for fluorinating (CF3)2CHOCH2Cl to produce (CF3)2CHOCH2F (Sevoflurane), which is a valuable inhalation anesthetic, especially useful in outpatient procedures and for conscious sedation.
There are many methods that can be used to synthesize fluorinated compounds such as Sevoflurane. One of the most useful is to first prepare the chloro-substituted compound, (CF3)2CHOCH2Cl (sevochlorane), the preparation of which is described in U.S. Pat. Nos. 3,476,860 and 3,683,092, followed by fluorination via a halogen exchange reaction. See Equation (1).(CF3)2CHOCH3→(CF3)2CHOCH2Cl→(CF3)2CHOCH2F  (1)
However, it has been found that the use of potassium fluoride in the halogen exchange reaction can be hampered by a low yield of fluorinated products, caused by, among other things, side reactions that produce elimination and hydrolysis products. In particular, when water is present in appreciable quantities, it has been found that hydrolysis products can be formed in large amounts, creating impurities that must be removed as well as severely reducing the yield of the desired fluorinated product.
For example, the reaction of chloroalkanes with potassium fluoride has been reported using a variety of methods. Landini, et al. (Synthesis, 1428 (1974)) reported the reaction of alkyl halides with potassium fluoride in the presence of phase transfer catalysts to yield alkyl fluorides. The reactions were not done with anhydrous potassium fluoride but were done in an aqueous medium. In this medium, there was significant hydrolysis to give alcohol by-products.
The effect of water on the reaction of potassium fluoride with halo-alkanes in the presence of phase transfer catalysts has been described by Dermeik, et al. (J. Org. Chem., Vol. 50, pp. 879-882, 1985). The reference indicates that low water content with respect to the fluorinating agent corresponds to low production of hydrolysis products. The data indicate that the potassium fluoride to water molar ratio must be greater than 15 in order for the hydrolysis products to fall to less than 4 mol % in the final product mixture.
Escoula, et al. (Tetrahedron Letters, Vol. 27, No. 13, pp. 1499-1500 (1985)) state that formamide is superior to water as a reaction medium for a fluoride-chloride exchange reaction employing phase transfer catalysts. Higher yields are obtained under these conditions.
Thus, if yield is important, the fluorination reaction has generally been performed in conditions under which the solvent is, at least predominantly, something other than water. For example, U.S. Pat. No. 3,683,092, mentioned above, describes the fluorination of (CF3)2CHOCH2Cl with potassium fluoride, using sulfolane (tetrahydrothiophene-1,1 dioxide) as a solvent; see Equation (2).

The references above generally concern the fluorination of chloroalkanes. One of skill in the art will recognize that in the case of chloroethers, the issue of hydrolysis in the presence of water to give ether cleavage is expected to be even more of a concern. In particular, 2-chloro-ethers are well known to be more easily hydrolyzed than alkanes in the presence of water. In other literature concerning the fluorination of chloroethers, the presence of water during fluorination of chloroethers is tightly controlled or scrupulously avoided to the point of complete elimination or avoidance.
The use of potassium fluoride as a reagent for the replacement of chlorine in organic compounds has been reviewed in M. Hudlicky, Chemistry of Organic Fluorine Compounds, 2nd Revised Edition, Ellis Horwood Ltd. (1992). The reference teaches that potassium fluoride has been successfully applied to the replacement of even poorly reactive halogen atoms, and that the success of this method lies in the application of suitable solvents such as acetamide, nitrobenzene, dimethyl sulfoxide, dimethyl sulfone, tetra methylene sulfone, and especially ethylene glycol and diethylene glycol. The reference also teaches that to obtain maximum yields, pure and absolutely dry (i.e., no water) chemicals must be used. The above is specifically taught with respect to halogen-containing ethers, among other things.
The fluorination of (CF3)2CHOCH2Cl using anhydrous potassium fluoride and without the addition of solvent is described in U.S. Pat. No. 4,874,901. The reaction is carried out at high temperatures (185° C.-283° C.). Reaction pressures as high as 1100 psig are disclosed. Sevoflurane is synthesized using this method, resulting in a 60% conversion and a 75% yield.
U.S. Pat. No. 6,100,434 also describes the effect of water on the fluorination of (CF3)2CHOCH2Cl. It discloses that, while the presence of water can be tolerated, high levels of water increase the likelihood of hydrolysis. Furthermore, the reference discloses that higher levels of water are likely to impede the fluorination reaction due to the relative immiscibility of the (CF3)2CHOCH2Cl in water. The reference also teaches that water, if used at all in the reaction, is used as a co-solvent (i.e., it is not used without the presence of another solvent material).
However, water is a convenient solvent to use. It is also often present in reactants and fluorinating agents that are commonly used in fluorination reactions, and in such cases, its presence during the fluorination reaction is difficult to avoid without extra purification steps. However, water is not as difficult to remove from reaction products as many other types of impurities. Thus, a high yield, low hydrolysis fluorination reaction of chloroethers, such as (CF3)2CHOCH2Cl, in an aqueous medium would be welcomed in the art.